5 - aryloxyatricyclo(3.2.2.0**2 4)nonane - 1-amines in antidepressant compositions and methods

ABSTRACT

5-PHENYL, 5-SUBSTITUTED PHENYL, 5-PYRIDYL, AND 5-SUBSTITUTED PYRIDYL OXATRICYCLO(3.2.2.024)NONAN-1-AMINES, AND N-CARBOALKOXY-5-PHENYL, 5-SUBSTITUTED PHENYL, 5-PYRIDYL, AND 5-SUBSTITUTED PYRIDYL OXATRICYCLO(3.2.2.324)NONAN-1AMINES AS ANTIDEPRESSANTS.

United States Patent O 3,657,439 5 ARYLOXYATRICYCLO[3.2.2.0 ]NNANE 1-AMINES IN ANTIDEPRESSANT COMPOSI- TIONS AND METHODS Paul E. Aldrich,Wilmington, Del., assignor to E. I. du Pont de Nemours and Company,Wilmington, Del. No Drawing. Original application Aug. 19, 1968, Ser.No. 753,727, now Patent No. 3,428,643. Divided and this application Aug.19, 1970, Ser. No. 65,290

Int. Cl. A61k 27/00 US. Cl. 424-263 8 Claims ABSTRACT OF THE DISCLOSUREphenyl, 5-substituted phenyl, S-pyridyl, and S-substituted pyridyloxatricyclo[3.2.2.0 ]nonan-1-amines, and N-carboalkoxy-S-phenyl,5-substituted phenyl, S-pyridyl, and 5-substitnted pyridyloxatricyclo[3.2.2.0 ]nonan-1- amines as antidepressants.

Examples of some compounds of this invention are; ethyl N 5-(4-pyridyl)3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane, 5 phenyl 3oxatricyclo[3.2.2.0 lnonane lamine, and 5 phenyl 3-oxatricyclo[3.2.2.0]nonane-lamine maleate.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisionof my copending application, Ser. No. 753,727 filed Aug. 19, 1968 whichin turn is a division of my earlier application, Ser. No. 641,412 filedMay 8, 1967, now U .8. Pat. 3,428,643.

BACKGROUND OF THE INVENTION This invention relates to novelS-aryloxatricyclo, 5-substituted aryloxatricyclo[3.2.2.0 nonan 1 aminesand -1-yl urethanes and their pharmaceutical use as antidepressants.

The synthesis of the compounds of this invention starts with4-arylbicyclo[2.2.2]oct-2-ene-1-carboxylic acids. The starting materialacids can be prepared through the addition of ethylene to theappropriate 6-aryl-a pyrone-3-carboxylate or to the appropriate3-aryl-u-pyrone-6-carboxy1- ate followed by alkaline hydrolysis.

*Organic chemical literature describes the preparation of the a-pyronesand the methods that are useful for the production of aromaticsubstituted a-pyrones. The following references give detailed proceduresfor the preparation of d-pyrones: Kochetkov et al., J. Gen. Chem. USSR(English Translation) 26, 643 (1956), 27, 277 (1957), and 28, 1562(1958) and 28, 2484 (1958) from acid chlorides; Wiley and Hart, J. Am.Chem. Soc. 76, 1942 (1959); Windholz et al., J. Org. Chem. 28, 1443(1963); anl Higgenbotham and Lapworth, J. Chem. Soc. 123, 1325 (1923).By the use of the above general processes With available startingmaterials, aromatic and substituted aromatic pyrones are easilyproduced.

The above obtained 4 aryl'bicyclo[2. 2.2]oct-2-ene-l-.

carboxylic acids can be converted to 4-arylbicyclo[2.2.2] oct-Z-en-l-ylurethanes by a modified Cuntius reaction [1. Org. Chem, 26, 3511 (1969)]in which a mixed anhydride of the acid is formed with ethylchloroformate and then is treated with sodium azide to form the acidazide, which when heated in toluene results in rearrangement to theisoeyanate. This isoeyanate is treated with an alcohol to form thecorresponding urethane.

SUMMARY OF THE INVENTION The compounds of this invention are representedby the formula 3,657,439 Patented Apr. 18, 1972 Ar- .m

o where R is H, methyl, and

9 .COR

where R is alkyl of 1 through 8 carbons, N,N-dimethyl-2- aminoethyl,ethylpyrrolidinyl, 2-methoxyethyl, benzyl, and Ar is l it COR wherein Ris alkyl of 1 through 4 carbons. These compounds are preferred due totheir favorable antidepressant activity 'in warm-blooded animals. Itwill be understood that the pharmaceutically acceptable salts of thosecompounds of this invention capable of salt formation are includedwithin the scope of this invention. Representative of thepharmaceutically acceptable salts are those having an anion derived fromacids such as hydrochloric acid, sulfuric acid, phosphoric acid, maleicacid, tartaric acid, or citric acid. The most preferred salts beingderived from hydrochloric acid or maleic acid.

Not all compounds of this invention, however, will form salts as a basicamine function must be present to enable salt formation to take place.Therefore, when Ar is a phenyl of Formula 2 where the R and R arehydrogen, methyl, ethyl chlorine, bromine, fiuorine, nitro, cyano,alkoxy or alkoxy carbonyl the R of Formula 1 must be hydrogen, methyl orCOR wherein the R is N,N dimethylaminoethyl or ethylpyrrolidinyl toallow formation of the basic amine salt. When Ar is a pyridyl of Formula3 salts can be formed with all the compounds of Formula 1 irrespectiveof the nature of the R of Formula 1.

Another aspect of the present invention is the use of a compound ofFormula 1 where Ar can be any of the compounds set out in Formula 2 andFormula 3 and R is COR where R is benzyl. This compound is particularlypreferred as an intermediate to be used to form those compounds of thisinvention where Ar is as set out in Formula 2 and Formula 3 and the R ofFormula 1 is H or methyl.

Another aspect of the present invention is the method of using the abovedescribed compounds to produce an antidepressant effect in warm-bloodedanimals.

In yet another aspect of this invention the compounds of this inventionare incorporated into pharmaceutical compositions such as tablets,capsules, suspensions and other like dosage forms for oraladministration, and solutions, suspensions, powders and other dosageforms for parenteral administration.

DESCRIPTION OETHE PREFERRED EMBODIMENTS I have discovered that the novelcompounds of Formula 1 surprisingly exhibit activity as antidepressantagents in warm-blooded animals.

The preparation of the -aryloxatricyclo[3.2.2.0 nonan-l-amines and theirN-carboalkoxy derivatives starts with the preparation of4-arylbicyclo[2.2.2]oct-2-ene-lcarboxylic acid from6-aryl-a-pyrone-3-carboxylic acid esters as illustrated by the followingpreparation of ethyl 4- phenylbicyclo [2.2.2] oct-2-en-1-earboxylate.

A mixture of 60 g. of 6-phenyl-apyrone-3-carboxylic acid ethyl ester and25 ml. of benzene is pressured to 1000 atmospheres with ethylene in ashaker tube at 200 C. for 16 hrs.

The shaker tube is cooled and the contents discharged, diluted with 500ml. of ethanol and filtered. The alcohol and benzene are distilled offleaving 57 g. of ethyl 4-phenylbicyclo[2.2.2]oct-2-ene-1-carboxylate asa white solid, M.P. 44-45.5 C.

Ethyl 6-phenyl-a-pyrone-3-carboxylate can be obtained by the method ofKochetkov et al., J. Gen. Chem. USSR (Eng. Tr.) 28, 1562 (1958), or asfollows: A suspension of 14 g. of sodium hydride in 300 ml. of anhydrousdimethylsulfoxide is stirred and warmed to 6070 C. The evolution ofhydrogen is measured with a wet test meter, and after the evolution iscomplete, the solution is cooled to 25 C. With stirring, 60.5 g. ofacetophenone is added, followed by 108 g. of diethylethoxymethylenemalonate. During these additions, the temperature is keptat 20-25 C. by cooling with an ice bath.

The mixture is allowed to stand for 1 hour, and then poured onto icecontaining 50 ml. of concentrated hydrochloric acid and 100 ml. ofdichloromethane. The dichloromethane layer is separated and the waterlayer extracted three times with diehloromethane. The dichloromethaneextracts are combined, dried with anhydrous magnesium sulfate, filtered,and the dichloromethane is removed by vacuum evaporation to give 135 g.of brown oil. This is combined with 300 ml. of xylene and heated toreflux under a distillation column with a reflux head. Ethanol isremoved as long as it forms. The xylene is then distilled at reducedpressure. Then, the mixture is heated at 125 C. and 0.3 mm., and allmaterial which is volatile at this temperature distills. The distillateis diluted with diethyl ether, whereupon the produce crystallizes. It isfiltered and dried to yield 35 g. of ethyl6-phenyl-a-pyrone-3-carboxylate, M.P. 106107 C.

The alkyl 4-arylbicyclo[2.2.2]oct-2-en-1-carboxylates, such as the ethyl4-pheny1bicyclo[2.2.2]oct-2-en-1-carboxylate obtained in theillustration, are converted to the free4-arylbicyclo[2.2.2]oct-2-en-1-carboxylic acids by alkaline or acidhydrolysis.

The starting 4-arylbicyclo[2.2.2]oct-2-en-1-carboxylic acid can beconverted to the desired 4-arylbicyclo[2.2.2j oct-Z-en-l-yl urethane bya modified Curtius reaction [J. Org. Chem, 26, 3511 (1961)] in which amixed anhydride of the acid is formed with ethyl chloroformate and isthen treated with sodium azide to form the acid azide. This is heated intoluene to cause rearrangement to the isocyanate, which is treated withan alcohol to form the desired urethane.

Although the above described modified Curtius reaction will mostconveniently prepare many of the compounds of this invention, a numberof 4-pyridylbicyclo[2.2.2]oct- 2-en-l-carboxylic acids are too insolubleto be converted to the isocyanate by this above described modifiedCurtius reaction. When this problem arises, the difficulty can beovercome by using the classical Curtius reaction in which the acidchloride of the 4-arylbicyclo[2.2.2]oct-2- en-l-carboxylic acid isprepared by conventional means and is then treated with sodium azide toform the acid azide; The acidazide i's refluxed with an alcohol'and abase such as triethylamine'to prepare the corresponding urethane.

The 4-arylbicyclo[2.2.2]oct-2-en-1-yl urethanes are dissolved in formicacid and treated with hydrogen peroxide to yield the corresponding3-oxatricyclo[3.2.2.0 ]nonanl-yl urethanes of this invention. When thearyl portion of the urethane is phenyl or substituted phenyl the 3-oxaring can also be introduced by treating the urethane with a peroxyacidin a neutral solvent, as for example mchloroperoxybenzoic acid inchloroform.

Catalytic reduction of benzyl N-5-aryl-3-oxatricyclo- [3.2.2.0]nonan-1-yl urethanes yield the 5-aryl-3-oxatricyclo[3.2.2O]]nonan-l-amines of this invention.

Reduction of 4 arylbicyclo[2.2.2]oct 2 en 1 yl urethanes with lithiumaluminum hydride yield the corresponding N methyl 4arylbicyclo[2.2.2]oct 2 enl-amines. Treatment of these methylamines withbenzyl chloroformate yields benzyl N-4-arylbicyclo[2.2.2]oct-2- en-l-ylurethanes which in turn are treated with hydrogen peroxide in formicacid or with m-chloroperoxybenzoic acid in an inert solvent such aschloroform to yield benzyl N-methyl-N-5-aryl-3-oxatricyclo[3.2.2.0]nonan- 1-yl urethanes. Catalytic reduction of the benzyl N-methyl- N 5aryl 3 oxatricyclo[3.2.2.0 ]nonan 1 yl urethanes yields thecorresponding N-methyl-5-aryl-3- oxatricyclo[3.2.2.0 ]nonan-l-arnines ofthis invention.

Illustrative of the compounds of this invention are the following:

Ethyl N-5-(4-pyridyl)-3-oxatricycl0[3.2.2.0 ]nonan- 1-yl urethane MethylN-5-(2,4-dimethylphenyl)-3-oxatricyclo [3.2.2.0 ]nonan-1-yl urethaneEthyl N-5-phenyl-3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane BenzylN-5-phenyl-3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane EthylN-5-(p-tolyl)-3-oxatricyclo[3.2.2.0 jnonan-l-yl urethane ButylN-S-(p-fluorophenyl)-3-oxatricyclo[3.2.2.0

nonan-l-yl urethane Isopropyl N-S-(2,4-difluorophenyl)-3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane IsopropylN-S-(p-chlorophenyl)-3-oxatricyclo [3.2.2.0 ]nonan-1-yl urethane n-OctylN-S-(p-bromophenyD-3-oxatricyclo[3.2.2.0

nonan-l-yl urethane Butyl N-5-(3-bromo-4-methylphenyl)-3-oxatricyclo[32.2.0 ]nonan-l-yl-urethane PropylN-S-(p-cyanophenyl)-3-0xatricyclo[3.2.2.0

nonan-l-yl urethane 2-methoxyethyl N-S-(p-nitrophenyl)-3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane EthylN-5-(p-methoxyphenyl)-3-oxatricyclo[3.2.2.0

nonan-l-yl urethane Methyl N-5-(p-methoxycarbonylphenyl)-3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane MethylN-5-(2,4-dimethoxycarbonylphenyl)-3-oxatricyclo[3.2.2.0 ]nonan-1-ylurethane fl-pyrrolidylethyl N-S-(m-fluorophenyl)-3-oxatricyclo [3.2.2.0]nonan-1-yl urethane Hexyl N-5-(m-bromophenyl)-3-oxatricyclo[3.2.2.0

nonan-l-yl urethane Methyl N-5-(m-nitrophenyl).-3-oxatricyclo[3.2.2.0

nonan-l-yl urethane Heptyl N-S-(m-methoxyphenyl)-3-oxatricyclo [3.2.2.0]n0nan-1-yl urethane Ethyl N-5-(o-tolyl)-3-oxatricyclo[3.2.2.0Jnonan-l-yl urethane Methyl N-S-(o-fluorophenyl)-3-oxatricyclo[3.2.2.0

nonan-l-yl urethane Methyl N-S-(o-chlorophenyl-3-oxatricyclo[3.2.2.0

nonan-l-yl urethane Propyl N-S- (o-bromophenyl) -3-oxatricyclo [3.2.2.0

nonan-l-yl urethane 2-methoxyethyl N-S-(o-nitrophenyl)-3-oxatricyclo[3.2.2.0 ]nonan-l-,yl urethane EthylN-S-(3,4-dirnethoxyphenyl)-3-oxatricyclo [3.2.2.0 ]nonan-1-yl urethaneHexyl N-5-(3-bromo-4-methoxyphenyl)-3-oxatricyclo [3.2.2.0 ]nonan-1-y1urethane Methyl N-5-(3-nitro-4-methoxyphenyl)-3-oxatricyclo [3.2.2.-]nonan-l-y1 urethane Ethyl N-- (3-pyridyl)-3-oxatricyclo [3.2.2.0nonanl-yl urethane Benzyl N-S- 3-pyridyl -3-oxatricyclo 3.2.2.0nonanl-yl urethane Butyl N-S-(Z-pyridyl)-3-oxatricyclo[3.2.2.0]nonanl-yl urethane Propyl N-S- 3-fluoro-4-pyridyl -3-oxatricyclo [32.2.0

nonan-l-yl urethane 2-methoxyethyl N-5-(5-ethyl-2-pyridyl)-3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane HexylN-5-(3-chloro-5-pyridyl)-3-oxatricyclo[3.2.2.0

nonaml-yl urethane v Methyl N-5-(5-ethoxy-3-pyridyl)-3-oxatricyclo [32.2.0 nonan-l-yl urethane 5-phenyl-3-oxatricyclo[3.2.2.0 ]nonan-l-amine5-( 3-pyridyl) -3-oxatricyclo [3.2.2.0 ]nonan-1-amine5-(4-pyridyl)-3-oxatricyclo[3.2.2.0 ]nonan-l-amineN-methyl-5-(4-pyridyl)-3-oxatricyclo[3.2.2.0 ]nonanl-amine N-niethylN-5-(4-chloro-3-pyridyl)-3-ox'atricyclo [3.2.2.0 ]nonan-1-amine 5-5-ethyl-2-pyridyl -3-oxatricyclo [3 2.2.0 nonanlamine5-(4-fluoro-3-pyridyl)-3-oxatricyclo[3.2.2.0 ]nonan-1- amineN-methyl-N-5- 3 -rnethoxy-2-pyridyl -3 -oxatricyclo [3.2.2.0]nonan-l-amine 5-(5-ethoxy-3-pyridyl)-3-oxatricyclo[3.2.2.0 ]nonan-1-amine S-(Z-pyridyl)-3-oxatricyclo[3.2.2.0 ]nonan-l-arnineN-methyl-5-phenyl-3-oxatricyclo[3.2.2.0 ]nonan-1- amine5-(4-methoxyphenyl) -3-oxatricyclo [3 .2.2.0 nonanlamine I 5-(4-fluorophenyl-3-oxatricyclo 3 2.2.0 nonanl-amine.

5-(4-chlorophenyl) 3 oxatricyclo[3.2.2.-0 ]n0nan-1- amine.

5-(4-brornophenyl) 3 oxatricyclo[3.2.2.0 ]nonan-1- amine.

N-methyl-S-(4-chlor0phenyl) 3 oxatricyclo[3.2.2.0

nonan-l-amine.

5-(p-to1yl)-3-oxatricyclo[3.2.2.0 ]nonan-l-amine.

5- (mtolyl) -3-oxatricyclo [3.2.2.0 ]nonan-1-amine.

5-(3,4-dimethylphenyl) 3 oxatricyclo[3.2.2.0 ]nonanl-amine.

S-(m-chlorophenyl) 3 oxatricyclo[3.2.2.0 ]nonan-1- amine.

5-(o-chlorophenyl) 3 oxatricyclo[3.2.2.0 ]nonan-1- amine.

5-(3,4-dichlorophenyl) 3 oxatricyclo[3.2.2.0 ]nonanl-amine.

S-(o-bromophenyl) 3 oxatricyclo[3.2.2.0 ]nonan-1- amine.

5-(3,4-dibromophenyl) 3 oxatricyclo[3.2.2.0 ]nonanl-amine.

to the following illustrative examples in which parts and 7 percentagesare by weight unless otherwise indicated.

EXAMPLE 1 Thionyl chloride (50 ml.) is dropped into a stirred refluxingmixture of 45.8 g. (0.20 mole) of 4-(4-pyridyl)-bicyclo[2.2.2]oct-2-ene-l-carboxylic acid and 150 ml. of ethylenedichloride. Refluxing is continued until all of the carboxylic acid isdissolved. The solution is allowed to cool and is evaporated. Theresidue is 4-(4-pyridy1)bicyclo[2.2.2]oct-2-ene-l-carboxylic acidchloride as evidenced by an infrared absorption band at 5.6;. (COC1).

The carboxylic acid chloride is stirred with 26.0 g. (0.4 mole) ofpulverized sodium azide in 250 ml. of acetonitrile for 16 hrs. The solidis filtered off and is dissolved in a mixture of water anddichloromethane. The dichloromethane layer is separated, is dried withanhydrous magnesium sulfate, and is combined with acetonitrile filtrate.The combined solutions are evaporated. The residue is4-(4-pyridy1)bicyclo[2.2.2]oct 2 ene-l-carboxylic acid azide asevidenced by infrared absorption bands at 4.67, (--N and at 5.86;.(-CO-).

The residue is refluxed with 200 ml. of alcohol and 20 ml. oftriethylamine for 16 hrs. The solution is evaporated. The residue ischromatographed on silicic acid (pH 7) with chloroform as the eluant.There is obtained ethyl N-4-(4-pyridyl)bicyclo[2.2.21oct 2 en 1 ylurethane, M.P. 141.5-142.5 C.

Analysis.Calcd. for C H N 0 (percent): C, 70.56; H, 7.40; N, 10.29.Found (percent): C, 71.51; H, 6.93; N, 10.28.

A solution of 0.080 mole of the above obtained ethyl N-4-(4-pyridyl)bicyclo[2.2.2]oct 2 en-l-yl urethane in ml. of formic acid is cooled inan ice bath, and 0.16 mole of 30% hydrogen peroxide is dropped in. Thesolution is stored at 5 C. for five days. The solution is then stirredwith 0.3 g. of 10% palladium on carbon for three hours. The catalyst isfiltered off and the filtrate is concentrated at reduced pressure. Theresidue is ethyl N 5-(4- pyridyl) 3 oxatricyclo[3.2.2.0 ]nonan-1-ylurethane. Recrystallization from ethyl acetate gives the urethane, M.P.l82-183.5 C.

Analysis.-Calcd. for C H N O (percent): C, 66.64; H, 6.99. Found(percent): C, 66.92; H, 7.07.

From the above example it will be apparent that by substituting 0.10mole of the appropriate 4-arylbicyclo [2.2.2] oct-2-en-1-carboxylic acidto the starting materials and substituting an appropriate alcohol duringthe ensuing reaction the desired N 4 arylbicyclo [2.2.2]oct-2-en-1-ylurethane starting material for the following examples will vbe obtained.

EXAMPLE 2 A solution of 0.08 mole of ethyl N-4-(3-pyridyl)-bicyclo[2.2.2]oct-2-en-1-yl urethane in 110 ml. of formic acid is cooled in anice bath, and 0.16 mole of 30% hydrogen peroxide is dropped in. Thesolution is stored at 5 C. for

five days. The solution is then stirred with 9.3 g. of 10% palladium oncarbon for 3 hours. The catalyst is filtered oif and the filtrate isconcentrated at reduced pressure. The residue is ethylN-S-(3-pyridyl)-3-oxatricyclo[3.2.2.0 nonan1-yl urethane, M.P. 187-188.5 C.

EXAMPLE 3 A solution of 0.08 mole of benzylN-4-(3-pyridyl)-bicyclo[2.2.2]oct-2-en-l-yl urethane in 110 ml. offormic acid is cooled in an ice bath, and 0.16 mole of 30% hydrogenperoxide is dropped in. The solution is stored at 5C. for five days. Thesolution is then stirred with 0.3 g. of 10% palladium on carbon for 3hours. The catalyst is filtered olf and the filtrate concentrated atreduced pressure. The residue is benzyl N-S-(3-pyridyl)-3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane, M.P. 126-127" C.

EXAMPLE 4 A solution of 0.08 mole of butyl N-4-(2-pyridyl)-bicyclo[2.2.2]oct-2-en-1-yl urethane in 110 ml. of formic acid is cooled in anice bath, and 0.16 mole of 30% hydrogen peroxide is dropped in. Thesolution is stored at 5 C. for five days. The solution is then stirredwith 0.3 g. of 10% palladium on carbon for 3 hours. The catalyst isfiltered off and the filtrate concentrated at reduced pressure. The

residue is butyl N-5-(Z-pyridyl)-3-oxatricyclo[3.2.2.0 nonan-l-ylurethane.

EXAMPLE 5 A solution of 0.08 mole of propylN-4-(3-fluoro-4-pyridyl)bicyclo[2.2.2]oct-2-en-1-yl urethane in 110 ml.of formic acid is cooled in an ice bath, and 0.16 mole of 30% hydrogenperoxide is dropped in. The solution is stored at 5 C. for five days.The solution is then stirred with 0.3 g. of 10% palladium on carbon for3 hours. The catalyst is filtered off and the filtrate concentrated atreduced pressure. The residue is propylN-5-(3-fluoro-4-pyridy1)-3-oxatricyclo[3.2.2.0 ]nonan-l-yl urethane.

EXAMPLE 6 A solution of 0.08 mole of ethylN-methyl-N-4-phenylbicyclo[2.2.2]oct-2-en-1-yl urethane in 110 ml. offormic acid is cooled in an ice bath, and 0.16 mole of 30% hydrogenperoxide is dropped in. The solution is stored at 5 C. for five days.The solution is then stirred with 0.3 g. of 10% palladium on carbon for3 hours. The catalyst is filtered off and the filtrate concentrated atreduced pressure. The residue is ethylN-methyl-N-5-phenyl-3-oxatricyclo[3.2.2.0 ]nonan-1-yl urethane.

EXAMPLE 7 A solution of 16 ml. (11.6 g., 0.115 mole) of triethylamine in100 ml. of acetone is added to a stirred mixture of 22.8 g. (0.10 mole)of 4-phenylbicyclo[2.2.2] oct-2-ene-1-carboxylic acid and 300 ml. ofacetone. This solution is cooled to -5 to C. and a solution of 12.0 g.(0.11 mole) of ethyl ehloroformate in 50 m1. of acetone is addeddropwise, With cooling, at a rate such that the temperature does notrise above 0 C. When the addition is complete, stirring is continued for30 min., and then a solution of 9.8 g. (0.15 mole) of sodium azide in 30ml. of water is added dropwise at to 0 C. After addition is complete,stirring is continued for 1 hour. The cold solution is diluted with iceWater and is extracted with toluene. The toluene solution is dried withanhydrous magnesium sulfate, is filtered, and is heated on a steam bathuntil the evolution of nitrogen is complete. Then, 0.10 mole of methanoland 5 ml. of triethylamine are added and the mixture is heated at refluxfor 16 hours. On cooling, the solution yields methyl N-4-phenylbicyclo[2.2.2]oct-2-en-1-yl urethane, M.P. 141.5-

A solution of 5.42 g. (0.020 mole) of ethylN-4-phenylbicyclo[2.2.2]oct-2-en-1-yl urethane and 4.15 g. (0.022 mole)of 86% m-chloroperoxybenzoic acid in 100 ml. of chloroform is stored atroom temperature, protected from light for four days. At the end of thisperiod, 0.3 g. of palladium on charcoal is added and the mixture isstirred for 2 hours. The catalyst is filtered off, and the filtrate isevaporated. The residue is triturated with a mixture of ether and 5%sodium hydroxide solution. The insoluble material is filtered ofi? andis discarded. The ether extract is dried with anhydrous magnesiumsulfate and is evaporated to give ethyl N-5-phenyl-3-oxatricyclo[3.2.2.0 lnonane-l-yl urethane. Recrystallization of the urethane fromcarbon tetrachloride yields crystals, M.P.

Analysis.Calcd. for C H NO (percent): C, 71.05; H, 7.37; N, 4.87. Found(percent): C, 71.79; H, 7.20; N, 5.42.

EXAMPLE 8 A solution of 0.020 mole of benzyl N-4-phenylbicyclo[2.2.2]oct-2-en-1-yl urethane and 0.022 mole of 86%m-ehloroperoxybenzoic acid in 100 ml. of chloroform is stored at roomtemperature and is protected from light for four days. At the end ofthis period, 0.3 g. of 10% palladium on charcoal is added and themixture is stirred for 2 hours. The catalyst is filtered off, and thefiltrate is evaporated. The residue is triturated with a mixture ofether and 5% sodium hydroxide solution. The insoluble nonan-l-ylurethane M.P. l36137.5 C.

EXAMPLES 9-30 Example 8 is repeated, substituting the indicated urethanereactant for that of Example 8 to obtain the product indicated.

Urethane reactant 0.020 mole Product oet-2-en-1-yl urethane.

trieyelo[3.2.2.0 ]-nenan-1-yl urethane.

10. Butyl N-4-(p-fluorophenyl) Butyl N-5-(p-fiuorophenyD-bieyelo[2.2.2]oet-2-en-l-yl 3-oxatrieyclo[3.2.2.0 4] urethane.nonan-l-yl urethane.

urethane.

urethane.

13.... Propyl N-4-(p-eyanophenyl)- PropylN-5-(p-eyanobieyclo[2.2.2]oct-2-en-1-yl phenyl)-3-oxatrieyelourethane.[3.2.2.0 ]nonan-1-yl urethane.

14...- 2-methoxyethyl N4-(p-nitro- 2-methoxyethyl N-5-phenyl)bieyelo[2.2.2]oct-2- (p-nitrophenyD-3- en-l-yl urethane.oxatrleyelo[3.2.2.0

nonan-l-yl urethane.

15. Ethyl N-4-(p-methexy phenyl) EthylN-fi-tp-methoxybieyel0[2.2.2]oet-2-en-1-yl pheny1)-3-oxatrlcyelourethane. [3.2.2.0' h1onan-l-yl urethane.

16. Methyl N-4-(p-methoxy- MethylN-fi-(p-niethoxyearbonylphenyl)bieyeloearb0nylphenyl)-3-[2.2.2]0et-2-en-1-yl urethane. oxatrleyelo[3.2.2.0 -4]-nonan-l-yl-urethane.

17. 2-dimethylaminoethyl N-4- 2-(1imethylaminoethyl-N-(m-tolyl)bieyelo[2.2.2]oet- 5(m-tolyl)-3-0xatricyel0- 2-en-1-ylurethane. [3.2.2.0 ]nonan-1-yl urethane.

l8. 2-pyrrolidy1ethyl N-4-(m- 2-pyrrolidylethylN-E-(mfiuorophenyl)blcyclo[2.2.2]- fluorophenyl)-3-oxatrt eyelooct-2-en-l-yl urethane. [3.2.2.0 ]nonan-1-yl urethane 19. CyelohexylN-4-(m-ehloro- Cyelohexyl N -5-(m-ehlorophenyl)bleyel0[2.2.2]0ct-2-phenyD-S-oxatrleyelw en-l-yl urethane. [3.2.2.0 ]nonan-1-yl urethane.

20. Hexyl N-4(m-bromophenyl)- Hexyl N-5-(m-bromophenyl)-bicyclo[2.2.2]oet-2-en-1-yl 3oxatricyelo[3.2.2.0 urethane. nonan-l-ylurethane.

21.... Methyl N-4-(m-nitrophenyD- MethylN-5-(m-r1itrobieye10[2.2.210et-2-en-1-y1 phenyl)-3-oxatrieyelourethane.[3.2.2.0 ]nonan-1-yl urethane.

22. Heptyl N-i-(m-methoxy- HeptylN-fi-(m-methoxyphenyl)bieyel0l2.2.2]oet-2- phenyD-Iiexatrlcyeloen-l-ylurethane. [3.2.2.0 ]nonan-1-yl urethane.

23- Ethyl N-4-(o-tolyl)bleyelo- Ethyl N-5-(o-tolyl)-3-[2.2.2]eet-2-en-1-yl urethane. oxatrleyel0[3.2.2.0

nenan-l-yl urethane.

24 Methyl N-4-(o-fluorophenyl)- Methyl N-S-(o-tluorrrbieyelo[2.2.2loet-2-en-1-yl phenyD-S-oxatrieyeltr urethane. [3.2.2.0-qnonen-l-yl urethane.

25. Methyl N-4-(o-ehlorophenyl)- Methyl N-5(o-ehlorobieyelo[2.2.2]oct-2-en-1-yl phenyl)-3-oxatrieyclo urethane.[3.2.2.0 ]nonan-1-yl urethane.

2G. Propyl N-4-(o-bromophenyl- Propyl N5-)obromobieyclol2.2.2]oet-2-en-l-yl phenyl)-30xatrieyclourethane. [3.2.2.0]nonan-1-yl urethane.

27, 2-rnethoxyethyl N-4-(0- Z-methoxyethyl N-5-(0-nitrophenyl)bieyclo[2.2.2] nitrophenyl)-3oxatrioet-2-en-1-yl urethane.eyelo[3.2.2.0 lnonanl-yl urethane.

28. Ethyl N-4-(3,4-dlrnethoxy EthylN-5-(3,4-dimethoxyphenyl)bieyelol2.2.2]octphenyl)-3-oxatrieyelo-2-en-1-yl urethane. [3.2.2.0 h10nan-l-y1 urethane.

20. Hexyl N4-(3-br0mo-4- Hexyl N-5-(3-bromo-4-methoxyphenyDbieyelemethoxyphenyl)-3-oxatrl- [2.2.2]oet-2-en-1-ylurethane. eyelol3.2.2.0 ]n0nanl-yl urethane.

30. Methyl N-4-(3-nitro-4- Methyl N-5-(3-nitro-4- methoxyphenyl)bieyelo[2.2.2]oct-2-en-1-yl urethane.

methoxyphenyl)3-oxatricyel0[3.2.2.0 ]nan-1- yl urethane.

A flask equipped with a stirrer is charged with 0.010 mole of benzylN-S-phenyl 3 oxatricyclo[3.2.2.0 ]nonane-yl urethane, 200 m1. ofalcohol, and 0.35 g. of 10% palladium on carbon. The flask is flushedwith hydrogen and the mixture is stirred. The reaction is continueduntil the efliuent gas no longer gives a positive test for carbondioxide with barium hydroxide solution. The catalyst is filtered off,and the filtrate is evaporated at reduced pressure. The residue is5-phenyl-3-oxatricyclo[3.2.2.0 ]nonane-l-amine. The amine ischaracterized as the maleate salt. The amine is dissolved in 40 ml. ofabsolute alcohol, and a solution of 0.010 mole of maleate acid in 20 ml.of alcohol is added. The mixture is cooled to C. and is allowed to standuntil crystallization is complete. The crystals are filtered off, arewashed with alcohol, and are dried to give -phenyl-3-oxatricyclo[3.2.2.0]nonane-lamine maleate salt, M.P. 202 C. (dec.).

Analysis.Calcd. for C14H17NO.C4H404 (percent): C, 65.24; H, 6.39. Found(percent): C, 65.15; H, 6.78.

EXAMPLES 32-43 Example 31 is repeated using the indicated urethane inplace of the benzyl N 5 phenylbicyclo[3.2.2.O ]nonane-l-yl urethane.

Ex. Reactant 32- Benzyl N-5-(3-pyridyl)-3- oxatricyclo[3.2.2.0 Jn0nan-1-yl urethane.

33. Benzyl N-5-(4-pyridy1) -3- oxatricyc1o[3.2.2.0 -nonan-1- yl methane.

34- Benzyl N5-(2-pyridyl)-3- oxatricyc1o[32.2.0 ]-nonan-1 yl urethane.

35. Benzyl N-5-(4-methoxy phenyl) 3-oxatrieyelo[3.2.2.0 ]-nonan- 1-ylurethane.

36. Benzyl N-5-(4-Iluorophenyl) oxatricyclo[3.2.2.02 .4]-nouanl-ylurethane.

87- Benzyl N -5-(4-chlorophenyl) 3-oxatricyelo[3.2.2.0 ]nonanl-ylurethane 38. Benzyl N-5-(5-bromophenyD- 3-oxatrieyelo[3.2.2.0 lmonanl-yl methane.

39. Benzyl N-G-(p-tolyl) -3-oxatrieyclo[3.2.2.0 ]nonan-1-yl urethane.

40- B enzyl N-S-(m-tolyl) -3-oxatricycl0[3.2.2.0 1nonan-1-yl urethane.

41 Benzyl N-5-(m-chlorophenyl) 3-oxatrieyc1o[3.2.2.0 ]nonan- 1-ylurethane.

42- Benzyl N-5-(-o-chlorophenyl)- 3oxatricyc1o[3.2.2.0]nonanl-yl-urethane.

- B enzyl N-5-(o-bron1opheny1)- 3-oxatricyclo [3.2.2.0 ]nonanl-ylurethane.

Product G-(S-pyridyl)'3oxatricyclo [3.2.2.0 ]nonan-1-amine[M.P

of maleate salt: 152C.

(dec 5-(4-pyridyl)-3-oxatricyelo [3.2.2.0 ]nonan-1-amine.

5-(2-pyridyl) -3-oxatricyclo [3.2.2.0 jlnonan-l-amine.

5-(4rnethoxyphenyl)3- oxatr1cyclo[3.2.2.0 lnonanl-amine.

5-(4-fluorophenyl)-3-oxatricyelo[3.2.2.0 lnonanJ-amme amine. 5-(p-toly1)-3-oxatricyc1o [3.2.2.0 ]nonan-1-amine.

5'(mt0lyl)-3-oxatricyclo [3.2.2.0 ]nonan-1-amine.

fi-(m-chlorophenyl)-3-oxatrieyelo[3.2.2.0 ]nonan-1- amine.

5-(0-chloropheny1) -3-oxatricyc l0[3.2.2.0 ]nonan-1- amine.

5-(obr0mophenyl)-oxatrieycl0[3.2.2.0 ]nonan-1 amine.

The urethane starting materials of this invention can be reduced withlithium aluminum hydride to give methyl-4-arylbicyclo[2.2.2]oct-2-ene-l-amines. These in turn are allowed toreact with benzyl chloroformate to yield the urethane. The urethane istreated with a peroxide to introduce the 3-oxa ring, and this compoundis in turn subjected to catalytic hydrogenation to yield the N-methylamine of this invention.

EXAMPLE 44 A mixture of 70 ml. of diethylene glycol dimethyl ether,0.050 mole of ethyl N-4-phenylbicyclo[2.2.2]oct-2- en-l-yl urethane, and0.10 mole of lithium aluminum hydride is heated at 120 C. with stirringunder a nitrogen atmosphere for 16 hours. The mixture is cooled andwater is added cautiously dropwise until hydrogen evolution is completeand the gray color turns to white. The insoluble material is filteredoff and is washed with diethylene glycol dimethyl ether. The filtrate ispoured into 500 ml. of H 0. The mixture is extracted with ether. Theether extract is dried with anhydrous potassium canbonateand isevaporated to give a residue, which is N-methyl-4-phenylbicyclo[2.2.2]oct-2-en-1-amine. The amine can be characterizedas its hydrochloride salt by dissolving it in hot solution of 20 ml. ofconcentrated hydrochloric acid in 230 ml. of water. When the solution iscooled, crystals of N methyl-4-phenylbicyclo[2.2.2]oct-2-en-l-aminehydrochloride separate.

To a solution of 0.040 mole of.N-methyl-4-phenylbicyclo[2.2.2]oct-2-en-1-amine in 200 ml. of benzeneis added 10 ml. of benzyl chloroformate and 10 m1. of triethylamine. Themixture is refluxed for 2 hours, is cooled, and is concentrated atreduced pressure. The residue is triturated with dilute hydrochloricacid. The insoluble material is filtered oil, is Washed with Water, andis dried to give benzyl Nmethyl-N-4-phenylbicyclo[2.2.2]oct-2- ene-1-ylurethane.

A solution of 0.04 mole of the above obtained benzyl N-methylN-4-phenylbicyclo[2.2.2]oct-2-en-l-yl urethane in 55 ml. of formic acidis cooled in an ice bath, and 0.08 mole of 30% hydrogen peroxide isdropped in. The solution is stored at 5 C. for five days. The solutionis then stirred with 0.1 g. of 10% palladium on carbon for three hours.The catalyst is filtered off and the filtrate is concentrated at reducedpressure. The residue is benzyl N-methyl-N-5-phenyl-3-oxatricyclo[3.2.2.O ]nonan 1 yl urethane.

A flask equipped with a stirrer is charged with 0.010 mole of benzylN-methyl-N-5-phenyl-3-oxatricyclo[3.2.2. 0 ]nonane-yl urethane, 200 ml.of alcohol, and 0.35 g. of 10% palladium on carbon. The flask is flushedwith hydrogen and the mixture is stirred. The reaction is continueduntil the effiuent gas no longer gives a positive test for carbondioxide with barium hydroxide solution. The catalyst is filtered oil,and the filtrate is evaporated at reduced pressure. The residue isN-methyl-5-phenyl-3- oxatricyclo[3.2.2.0 ]nonane-l-amine. The amine ischaracterized as the maleate salt. The amine is dissolved in EXAMPLES 45AND 46 Example 44 is repeated substituting 0.050 mole of the indicatedstarting material for the ethyl N-4-phenylbicyclo[2.2.2]oct-2-en-1-ylurethane to yield the indicated N-methyl amine.

Ex. Starting material 45. Ethyl N-4-(4-pyridy1)bieyclo[2.2.2]0ct-2-en-1-y1 urethane.

46. Methyl N-4-(4-chlorophenyD- bicycle[2.2.2.]oct-2-en-1-yl ureth ane.

Product N-methyl-5-(4-pyridy1-3- oxatrieyclo[3.2.2.0 ]nonanl-amine.

N-methyl-5-(4-chlorophenyl)- 3-oxatricyclo[3.2.2.0 ]nonanl-amine.

The procedure of Examples 1 through 6 may be used to prepare the phenyland substituted-phenyloxatricyclo- [3.2.2.0 ]nonane-1-yl urethanes of myinvention as well as the pyridyl and substituted-pyridyloxatricyclo[3.2.2.0 ]nonane-1-yl urethanes of my invention. The procedure of Examples 7through 30, however, i unsatisfactory for the preparation of the pyridyland substitutedpyridyloxatricyclo[3.2.2.0 ]nonane-1-yl urethanes of myinvention because of the formation of pyridyl N-oxides.

The preceding examples can be repeated substituting equivalent amountsof appropriate starting materials to obtain other compounds of thisinvention including those listed hereinbefore.

The com-pounds of this invention can be administered to Warm-bloodedanimals for antidepressant etfect according to this invention by anysuitable means. For example, administration can be parenteral, that issubcutaneous, intramuscular, or intraperitoneal. Alternatively orconcurrently, administration can be by the oral route.

The dosage of compounds of this invention administered to thewarm-blooded animal will depend on the age, health and weight of thesaid warm-blooded animal recipient, the frequency of administration andthe intensity of the antidepressant response desired. Generally, a dailydosage of active ingredient compound will be from about 0.05 to 50 mg.per kg. of body weight, although lower, such as 0.01 mg. per kg., orhigher amounts can be used. Ordinarily, from 0.1 to 20 and preferably0.1 to mg. per kg. of body weight per day, in single or divided dosesand preferably in divided doses, is effective to obtain the desiredantidepressant response.

Ethyl N-5- (4-pyridyl) -3 -oxatricyclo [3 2.2.0 nonanlyl urethane, acompound of this invention, strongly indicates antidepressant activityas demonstrated in tests conducted on white mice in which a single doseof the above named compound, administered orally in a dose of 2 mg. perkg. of body weight, demonstrates successful protection againsttetrabenazine-induced sedation.

Besides the active ingredient of this invention the composition willcontain a solid or liqud non-toxic pharmaceutical carrier for the activeingredient.

One embodiment of a pharmaceutical composition of this invention is agelatin capsule for oral administration containing from about 1-50% of a4-aryloxatricyclo[3.2. 2.0 ]nonane-1-amine of this invention and 99-50%of a carrier. In another embodiment, the active ingredient is tabletedwith or without adjuvants. In yet another embodiment, the activeingredient is put into powder packets and employed. These capsules,tablets and powders will generally constitute from about 1% to about 95%and preferably from 1% to 50% by weight of active ingredient. Thesedosage forms contain from about 1 to 500 mg. of active ingredient, withfrom about 1 to about 100 mg. most preferred.

The pharmaceutical carrier can, as previously indicated, he a sterileliquid such as water and oils, including those of petroleum, animal,vegetable or synthetic origin, for example peanut oil, soybean oil,mineral oil, sesame oil, and the like.

In general, water, saline, aqueous dextrose and related sugar solutionsand glycols such as propylene glycol or polyethylene glycols are thepreferred liquid carriers for injectable solutions when the salts of theactive ingredient are to be administered. When a parenteral dosage formof the free base, especially those compounds of this invention that donot readily form pharmaceutically acceptable salts, is desired, thoseoils hereinbefore enumerated are the most preferred pharmaceuticalcarriers.

The sterile parenteral dosage forms mentioned above will ordinarilycontain from about 0.05% to and preferably about 0.1% to 1% by weight ofthe active ingredients.

In yet another embodiment of a pharmaceutical composition the activeingredient can be prepared for oral administration by incorporating itinto a suitable liquid pharmaceutical carrier such as an aromatic water,elixir, syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in RemingtonsPharmaceutical Sciences by E. W. Martin a well known reference text inthis field.

In addition to the exemplary illustrations above, the following examplesfurther explain one aspect of the present invention.

EXAMPLE 47 A large number of unit capsules are prepared for oraladministration by filling standard two-piece hard gelatin capsules with50 milligrams of powdered 5-(3-pyridyl)-3- oxatricyclo[3.2.2.0]nonan-l-amine, maleate, 125 milligrams of lactose and 1 milligram ofCab-O-SiI finely divided silica.

EXAMPLE 48 A large number of compressed tablets are prepared byconventional procedures so that the dosage unit is 5 12 milligrams ofactive ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesiumstearate and milligrams of lactose.

EXAMPLE 49 A parenteral composition suitable for administration byinjection is prepared by mixing 0.25% by weight of ethylN-5-phenyl-3-oxatricyclo[3.2.2.O ]nonan-1-yl urethane with sterilesoybean oil.

A large variety of compositions according to this invention can be thusreadily made by substituting ot er compounds of this invention, andincluding specfically, but not limited to, compounds of this inventionthat have specifically been named hereinbefore. The compounds will beused in the amounts indicated in accordance with procedures well knownand described in the E. W. Martin text mentioned above.

The above and similar examples can be carried out in accordance with theteachings of this invention, as will be readily understood by personsskilled in the art, by substitution of components and amounts in placeof those specified. Thus, the foregoing detailed description has beengiven for clearness of understanding only and no unnecessary limitationsare to be understood therefrom.

I claim:

I. A method of producing an antidepressant effect in a warm-bloodedanimal comprising administering to said warm-blooded animal anantidepressant effective amount of a compound of the formula:

where R is selected from the group consisting of hydrogen and methyl;and Ar is a group of the formula where R; is hydrogen, methyl, ethyl,chlorine, bromine,

fluorine methoxy and ethoxy; and

a pharmaceutically acceptable salt of a compound of the above formula.

2. A method of producing an antidepressant effect in a warm-bloodedanimal comprising administering to said warm-blooded animal anantidepressant effective amount of 5-(3-pyridyl)-3-oxatricyclo[3.2.2.0]nonane-l-amine.

3. A method of producing an antidepressant effect in a warm-bloodedanimal comprising administering to said warm-blooded animal anantidepressant effective amount of 5-(3-pyridyl)-3-oxatricyclo[3.2.2.0]t1onane-1-amine hydrochloride.

4. A method of producing an antidepressant effect in a warm-bloodedanimal comprising administering to said warm-blooded animal anantidepressant effective amount of 5-(3-pyridyl) 3 oxatricyclo[3.2.2.0]nOnane I-amine maleate.

5. A pharmaceutical composition comprising an antidepressant effectamount of a compound of the formula where R is selected from the groupconsisting of hydrogen and methyl; and Ar is a group of the formulawhere R; is hydrogen, methyl, ethyl, chlorine, bromine,

fluorine, methoxy and ethoxy; and

a pharmaceutically acceptable salt of a compound of the above formula;in combination with (b) a pharmaceutically acceptable diluent.

6. A pharmaceutical composition of claim 5 in which the activeingredient is 5 (3 pyridyl)-3-oxatricyclo [3.2.2.0 ]-nonane-1-amine.

7. A pharmaceutical composition of claim 5 in which the activeingredient is 5 (3 pyridyl)-3-oxatricyclo 3.2.2.0 -nonane-1-aminehydrochloride.

8,. A pharmaceutical composition of claim 5 in which the activeingredient is 5 (3 pyridyl)-3-oxatricyc1o [3.2.'2.0 ]-nonane-l-arninemaleate.

5 STANLEY I. FRIEDMAN, Primary Examiner US. Cl. X.R.

